Process for the preparation of {60 -hydroxy-{62 -phenypropionic acid derivatives and alkalimetal-or ammonium salts thereof

ABSTRACT

Alpha -Hydroxy- Beta -phenylpropionic acid derivatives having the formula   WHEREIN R1&#39;&#39; and R2&#39;&#39; are a benzyloxy group or the same as R1 and R2 provided that when R1 and R2 are a hydroxy group, R1&#39;&#39; and R2&#39;&#39; represent a benzyloxy group, R3 is the same as above and M represents an alkali metal or ammonium to a catalytic reduction in the presence of an organic polar solvent such as methanol and acetone.   WHEREIN R1 and R2 represent a hydroxy group or a methoxy group or R1 and R2 taken together represent a methylenedioxy group and R3 represents a hydrogen atom or a methyl group and alkali metalor ammonium salts thereof which are useful as intermediates for the synthesis of L- Alpha -methyl- Beta -(3,4-dihydroxyphenyl)alanine and L- Beta -(3,4-dihydroxyphenyl)alanine. The propionic acid derivatives and the salts thereof are prepared by subjecting a Beta -phenylglycidic acid derivative having the formula

United States Patent [191 Nagoya et al.

[451 Apr. 3, 1973 [54] PROCESS FOR THE PREPARATION OFa-HYDROXY-BPHENYPROPIONIC ACID DERIVATIVES AND ALKALIMETAL-OR AMMONIUMSALTS THEREOF [75] Inventors: Tsutomu Nagoya, Ashigarashimogun; YoshitoFujima, Kamakura; Yoichi Shimizu, Yokohama, all of Japan [73] Assignee:Sankyo Chemical Industries Limited [22] Filed: Sept. 16, 1970 [21] Appl.No.: 72,903

[52] US. Cl. ..260/340.5, 195/104, 260/141,

' 260/348, 260/521 R, 424/282 [51] Int. Cl. ..C07d 13/10 [58] Field ofSearch ..260l340.5, 521 B, 473 A [56] References Cited UNITED STATESPATENTS 7/1966 McClure ..260/473 A OTHER PUBLICATIONS Hueter, ChemicalAbstracts," Vol. 57 (1962), Col. 12326d.

Primary Examiner-Donald G. Daus Assistant Examiner-James H. Turni'pseedAttorney- Mc Glew and Toren wherein R, and R represent a hydroxy groupor a methoxy group or R, and R taken together represent a methylenedioxygroup and R represents a hydrogen atom or a methyl group and alkali'metalor ammoni- I um salts thereof which are useful as intermediatesfor the synthesis of L-a-methyl-B-(Ii,4-dihydroxyphenyl)- alanine andL-B-(3,4-dihydroxyphenyl)alanine. The.

propionic acid derivatives and the salts thereof are prepared bysubjecting a fi-phenylglycidic acid deriva tive having the formula v n,'m'-- 0n( ;00M

wherein R, and R are a benzyloxy group or the same as R, and R providedthat when R, and R, are a hydroxy group, R, and R, represent a benzyloxygroup, R is the same as above and M represents analkali metal orammonium to a catalytic reduction in the presence of an organic polarsolvent such as methanol and acetone.

. 3Claims,No Drawings This inventionrelates to an improved process forthe preparation of a-hydroxy-B-phenylpropionic acid derivatives havingthe formula wherein R and R represent a methoxy group or R, and R takentogether represent a methylenedioxy group hydroxy-B-phenylpropionic acidderivatives and the salts thereof obtained by the present invention areknown compounds and useful.asintermediatesfor the synthesis ofL.-a-,methyl-B-( 3 ,4-dihydroxyphenyl)alanine and L.-B(3,4-dihydroxyphenyl) alanine which are which are known as anantihypertensive agentor an antiparkinsonian drug. For instance, L-B-(3,4-dihydroxyphenyl)alanine. is prepared by. aminating and R representsa hydrogenatomor a methyl group and alkali'metalor ammonium saltsthereof. The athe B-phenylpropionic acid derivative bythe'action ofBrevibacterium ammeniagene s to give only the L- :isomer of the aamino-fi phenylpropionic'acid' derivative and, if necessary,hyd'rolyzingthe latter compound with hydrobromic acid. -And,L-a-methyI-B-(SA- dihydroxyphenyl)alanine is prepared by halogenatingthe 'L -a-methyl-Bphenylpropionicacid vderivative'vvith -thionyl halide,for example, thion'yl chloride to give L- rz-halogeno-oz-methy]-B-phenylpropionic acid derivative, aminatingthe latter compoundwithammonia -to give'the L-a-me'thyl fl-phenylalanine derivativeand, ifnecessary, hydrolyzingthelatter compound.

Heretofore a process for the preparation of I the propionic acidderivative (-1) has been provided by Gottfried Faust et al., in'EastGermanPat'. No. 53,701. According to the prior-process, they may beprepared bydiazotizing 4-.aminoveratrolwith sodium nitrite, subjectingthe diazonium compound to a couplingreaction with acrylonitrileormethacrylonitrile and hydrolyzing the coupling product with sulfuricacid; However, the prior process is commercially disadvantageous,

because the yield in the coupling reaction is extremely wherein R, andR, are a benzyloxy group or-the same as R, and R5 provided that .when Rand R, are a hydroxy group, R and R, areabenzyloxygroup, R, is

- ,ethanol to give crystals of the'desired product as an'alkalimetal orammonium salt. When'the free acid (I) is the same as above and Mrepresents an alkali metal or ammonium to a catalytic reductionin thepresence of an organic polar solvent.

Incarrying out the present invention, the B-phenylglycidic acidderivatives (II) and a catalyst are advantageously suspended in theorganic polar solvent and the suspension is contacted with hydrogen gasby a conventional means, for example, stirring orbubbling at an ordinarytemperature and pressure. As the catalyst, there may be employed anycatalyst that would be employed in a usual catalytic reduction.Preferably there may be employed palladium on carbonand a Raney nickelcatalyst. The fi-phenylglycidic acid derivatives (II) are sparinglysoluble in'an organic solvent. In the present invention, there may -bepreferably employed such a polar organic solvent that would'dissolve alarge amount ofthe derivatives-(II) as far as possible. When a polarorganic solvent scarcely dissolves the derivatives (II), the solventcontaining" a suitable amount of water is preferably employed. But thewater content is preferably low as far as possible, because thederivatives (II) are decomposed to phenylac'etoaldeh'yde derivativesbythe presence of water. Representative examples of the solvent employedin this-invention are methanol, ethanol, acetone, methyl ethyl ketoneand dioxane. Most preferably there may be employed-methanol. Thereaction'tem'p'erature and preferable'to'carry out the reaction at alower tempera; time After completion of the reaction, the'desiredproduct is recovered by a'conventional means. For in-. stance, thereaction mixture is filtered to remove the catalyst and'the'filtrate isconcentrated to dryness. The

residue is washed with a suitable solvent such as desired, a'smallamount of water is'added to the residue r obtained as above and amineral acid such as sulfuric acid and hydrochloric acid is added totheaqueous d erivative'fll) is converted-tea hydroxy group by thecatalytic reduction during the reaction in this invention.

According to the presentv invention, the desired products (I) maybeeasily prepared from the B-phenylglycidic acid derivatives withsuch ahigh *yieldas above percent. Furthermore, the fl phenylglyeidic' acid.mercially advantageous.

Representative examples of the desired products in this invention are asfollows; Y Y

a-hydroxy-fi-( 3 ,4-dimethoxyphenyl)propionic acid,a-hydroxy-a-methyl-B-(3,4-dimethoxyphenyl)propionic acid,a-hydroxy-B-(3,4-m-ethylenedioxypheriyl)propionic acid,

ac id Example 1.

7.38 g. of sodium B-(3,4-dimethoxyphenyl)glycidate are suspended in 100ml. of 98 percent methanol. To the suspension is added 0.7 g. of percentpalladium on carbon. The resulting mixture is contacted with hydrogengas at 25C under atmospheric pressure with stirring. After 30 minutesthe absorption of hydrogen gas ceases and the reaction is over. Thecatalyst is filtered off from the reaction mixture and the filtrate isconcentrated to dryness. To the residue is added a small amount of waterand the aqueous solution is made acidic by addition of hydrochloric acidto give 6.20 g. (91.5 percent yield) of a-hydroxy-B-(3,4-dimethoxyphenyl)propionic acid as crystals melting at 123 124C.

Example 2.

5.75 g. of sodium [3-(3,4-methylenedioxyphenyl)glycidate are suspendedin 80 ml. of 99 percent methanol and 0.5 g. of a Raney nickel catalystis added to the suspension. The resulting mixture is contacted withhydrogen gas at 25C under atmospheric pressure with stirring. Aftercompletion of the reaction, the

' reaction mixture is treated with the same procedure as in Example 1 togive 4.88 'g. (93 percent yield) ofahydroxy-[H3,4-methylenedioxyphenyl)propionic acid melting at 95 96C.

Example 3.

Example 4.

22.1 g. of sodium B-(3,4-dibenzyloxyphenyl)glycidate are suspended in203 ml. of 99 percent methanol. To the suspension are added 2.2 g. of 5percent palladium on carbon. The resulting mixture is contacted withhydrogen gas at 25C under atmospheric pressure with stirring. After 30minutes the absorption of hydrogen gas ceases and the reaction is over.

The catalyst is filtered off from the reaction mixture and the filtrateis concentrated to dryness. To the residue are added 47 ml. of percentethanol to give 10 g. (82.0 percent yield) of sodium a-hydroxy-B-(3,4-dihydroxyphenyl)propionate as crystals melting at 226 227C. The productthus obtained is treated with hydrochloric acid to givea-hydroxy-B-(3,4-dihydroxi'5i1z-ltliil%?fi2.' me'tmg 1. A process forthe preparation of a a-hydroxy-B- phenylpropionic acid derivative havingthe formula phenylglycidic acid derivative having the formula R3 R1CH(IJ-COOM wherein R, and R, are a benzyloxy group or the same as R, andR provided that when R, and R, are a hydroxy group, R and R, are abenzyloxy group, R is the same as above and M represents an alkali metalor ammonium to a catalytic reduction in the presence of an organic polarsolvent and hydrogen gas, the catalyst for the catalytic reduction beingpalladium on carbon or a Raney nickel catalyst.

2. A process as claimed in claim 1 wherein said organic polar solvent ismethanol.

3. A process as claimed in claim 1 wherein the catalytic reduction iscarried out at an ordinary temperature and pressure.

i I I l UNITED STATES PATENTGFFICE- CERTIFECATE ECTION Patent No. 3 7Z5437 Dated April 3 1973 I t Tsutomu Nagoya et a1 It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

In the heading of the patent, insert:

-- [30] Foreign Application Priority Data September 25, 1969 Japan.76.463/69-- Signed and sealed this 19th day of March 197M.

(SEAL) Attest:

EDWARD M.FLETCHER, JR. 0. MARSHALL DANN Attesting Officer 7 Commissionerof Patents USCOMM-DC 60376-P69 FORM P0-1050 (10-69) w 0.5. GOVERNMENTPRINTlNG OFFICE we, o-asa-au,

2. A process as claimed in claim 1 wherein said organic polar solvent ismethanol.
 3. A process as claimed in claim 1 wherein the catalyticreduction is carried out at an ordinary temperature and pressure.